1. American Venous Forum 2014
26th Annual Meeting
February 19-22, 2014
New Orleans, LA
Pharmacokinetics and Electrocardiac Effects of Polidocanol Injectable Foam in Humans
Eulogio J. Sanchez, MD
The Cardiovascular and Vein Center, Bradenton, Florida
Introduction
– Currently, there is no available data concerning the pharmacokinetics
(PK) of sclerosants injected as foam. Previous assays were not sensitive
enough to detect circulating polidocanol levels.
– Polidocanol injectable foam is indicated for the treatment of patients with
incompetent veins and visible varicosities of the great saphenous vein
(GSV) system.
– This foam is formulated with a gas mixture (oxygen:carbon dioxide in a
ratio of 65:35 with low [<0.8%] nitrogen content) by a pressurized
canister system designed to create consistent physical foam
characteristics while allowing for rapid bubble absorption following
injection into the vein.
– Polidocanol injectable foam has been studied in several nonclinical and
clinical studies and has been used to treat chronic venous insufficiency
of the GSV using doses up to 60 mL per treatment session.
– Polidocanol has a long history of use as a local anesthetic with cardiac
effects.
Overall Study Design
– 5-week, open-label, single-center study of polidocanol injectable foam in
patients with incompetence of the saphenofemoral junction (SFJ)
associated with incompetence of the GSV or other major accessory vein
conducted in the United States;
– 21 patients with SFJ incompetence and reflux of the GSV or other major
accessory vein with venous disease manifested by visible varicosities
were randomly assigned in a 1:1 ratio by gender to receive a fixed 10 mL
dose of either polidocanol injectable foam 1% or 2% administered as two
5 mL injections, 10 minutes apart;
– Serial 12-lead Holter Electrocardiogram (ECG) monitoring was
conducted, blood and urine were measured, and urine was collected
during the 8 hours following treatment;
– Patients were discharged after 8 hours and reviewed at 1 week;
additional treatment was given if treatment was incomplete;
– Blood and urine were assayed for polidocanol by liquid chromatography
and tandem mass spectrometry (Simbec Research Ltd , UK), giving
lower limit of detection of 50 ng/mL.
Study Conduct
– This study was conducted in compliance with the Declaration of Helsinki
and Good Clinical Practice, International Conference on Harmonization
standards; Institutional Review Board approval; all patients gave signed
consent.
– Determine the PK parameters of polidocanol following fixed treatment
with polidocanol injectable foam, including Cmax, Tmax, AUC, clearance,
terminal rate constant, volume of distribution, and elimination half-life,
after administration of 10 mL 1% or 2%.
Primary Endpoints
– Measurements of the plasma concentrations of 4 major polidocanol
oligomers (E5, E9, E12, and E14) to derive the following PK parameters
for total polidocanol and the oligomers: maximum concentration of drug in
the body after dosing (Cmax), time to maximum concentration (Tmax), area
under the curve (AUC), elimination rate constant (Kel) terminal
elimination half-life (T1/2), clearance (CL), and volume of distribution (Vd).
Other Endpoints
– Analysis of ECGs collected before and at multiple time points up to and
including 8 hours following treatment.
Safety
– Patients were monitored for adverse events (AEs).
Objectives
Methods
Data Analysis
Results
Demographic Characteristics
– 21 patients were randomized and treated: 3 male and 6 female patients
received 1% polidocanol injectable foam, and 6 male and 6 female
patients received 2% polidocanol injectable foam. Although a higher
number of female patients received 1% polidocanol injectable foam,
baseline demographics were similar between treatment groups, with
the exception of differences in body weight between male and female
patients.
Summary of Patient Demographics
Parameter
Baseline Demographic Characteristics
Polidocanol
Injectable Foam
1%
(N=9)
Polidocanol
Injectable Foam
2%
(N=12)
All
Patients
(N=21)
Age, yrs (SD) 54.0 (9.62) 49.9 (11.4) 51.7 (10.6)
Height, cm (SD) 170.5 (14.11) 174.6 (12.45) 172.8 (13.01)
Weight, kg (SD) 78.6 (10.15) 84.0 (22.99) 81.7 (18.4)
BMI, kg/m2 (SD) 27.1 (2.52) 27.1 (5.19) 27.1 (4.16)
Ethnicity, n (%)
Hispanic or Latino
Non-Hispanic or
Latino
1 (11.1)
8 (88.9)
0
12 (100.0)
1 (4.8)
20 (95.2)
*yrs = years; m = meter; kg = kilogram; n = number, SD = standard deviation
This study was sponsored by BTG International Inc.
BTG and the BTG roundel logo are registered trademarks of BTG International Ltd
Polidocanol Injectable
Foam
1%
Polidocanol Injectable
Foam
2%
Male
(n = 3)
Female
(n = 6)
Male
(n = 6)
Female
(n = 6)
Weight
(kg)
Mean 90.30 72.95 99.92 65.55
SD 4.67 6.04 15.00 19.29
Summary of Body Weight by Gender
kg = kilogram; n= number
Pharmacokinetics
– Polidocanol (total and oligomer E5, E9, E12, and E14) first peaked
within 10 minutes of the first injection and 5 minutes following the
second polidocanol injectable foam injection, reaching Cmax within 15
minutes of the first injection.
– Overall polidocanol exposure was higher in female than male patients;
however, weight-normalized data demonstrated no consistent
differences in mean Cmax or AUC values between males and females.
– The rise in plasma polidocanol concentrations was less than proportional
to increasing polidocanol injectable foam dose concentration.
– The mean terminal elimination half-life, t1/2, ranged from102 to 153
minutes across treatment groups, with the majority of polidocanol being
eliminated from plasma within approximately 120 minutes.
– Mean Vd and CL were similar in male and female patients.
– Less than 0.02% of dose was recovered in urine.
– AUC of oligomers E9, E12, and E14 were approximately 2-fold greater
than those of oligomer E5.
Summary of Select PK Parameters for Total Polidocanol
Following Polidocanol Injectable Foam 1% and 2.0% by Gender
Parameter Polidocanol
Injectable Foam 1%
Polidocanol
Injectable Foam
2%
Male
(n=3)
Female*
(n=6)
Male**
(n=6)
Female***
(n=5)
Terminal
elimination
Half-life
(t1/2; min)
Mean
SD
102.0
10.5
105.5
21.5
153.4
58.6
114.1
46.1
CL (L/min) Mean
SD
0.288
0.095
0.236
0.078
0.351
0.115
0.291
0.072
Vd (L) Mean
SD
41.8
11.9
34.9
9.8
82.4
52.9
48.0
23.5
Ae[0-4hrs] (ng) Mean
SD
NC 2394.8
2252.3
1497.9
2051.0
3180.1
1641.3
Ae (% dose) Mean
SD
NC 0.018
0.017
0.007
0.008
0.012
0.006
Renal
Clearance
Mean
SD
0.053
0.057
0.034
0.035
0.043
0.030
* n = 4 females for Ae and Ae% following Varithena™ 1%
** n = 4 males for Ae and AE% following polidocanol injectable foam 2%
*** n = 5 females for Ae and Ae%; AUC[0-t] where t = 300 min; ng = nanogram;
min = minute; mL = milliliter; L = Liter NC = Not calculable, no polidocanol detected
in urine; Ae=amount excreted.
Safety
– Both polidocanol injectable foam doses concentrations were well
tolerated.
– The majority of AEs were mild and resolved without sequelae.
– A review of the ECG data revealed no significant effect of polidocanol
injectable foam on cardiac repolarization.
Conclusions
Acknowledgments
Oligomer Parameter Polidocanol
Injectable Foam
1%
Polidocanol
Injectable Foam
2%
Male
(n=3)
Female
(n=6)
Male
(n=6)
Female
(n=5)
E5 AUC 0-t
(ng.min/mL)
Mean
SD
1097.9
195.4
1019.9
215.1
1994.6
867.5
1776.7
354.4
AUC 0-inf
(ng.min/mL)
Mean
SD
1586.5
412.7
1639.9
451.1
3651.6
1981.9
2491.3
660.9
E9 AUC 0-t
(ng.min/mL)
Mean
SD
5122.1
2257.6
5465.8
1755.1
8424.1
3279.9
7467.2
1443.5
AUC 0-inf
(ng.min/mL)
Mean
SD
6084.2
2914.6
6315.5
2133.4
11430.4
4844.0
8256.6
1546.2
E12 AUC 0-t
(ng.min/mL)
Mean
SD
3904.8
1202.0
4182.3
1252.7
6236.1
2222.8
5654.0
1196.3
AUC 0-inf
(ng.min/mL
Mean
SD
4877.8
1717.6
5008.4
1803.3
8819.7
3644.3
6464.5
1342.8
E14 AUC 0-t
(ng.min/mL)
Mean
SD
1907.2
409.8
2154.0
458.2
3314.8
1172.0
3243.8
675.2
AUC 0-inf
(ng.min/mL
Mean
SD
3166.3
556.9
2807.8
747.9
5493.1
2551.9
4136.0
876.0
– Polidocanol injectable foam 1% and 2% demonstrated consistent and
reproducible pharmacokinetics.
– Differences between male and female patients were attributed to
differences in body weight.
– Both polidocanol injectable foam dose concentrations were generally
well tolerated.
The author gratefully acknowledges Dorothy L. Tengler of
BTG International Inc. for medical writing assistance.
Summary of PK AUC for Oligomers E5, E9, E12, and E14
Following Polidocanol Injectable Foam 1% and 2% by Gender
(Weight Normalized)
AUC=area under the curve; AUC0-t=AUC from time zero to last time point; AUC0-
inf=AUC from time zero to time infinity; SD= standard deviation; Ng=nanogram;
min=minute; mL=milliliter